JP6475618B2 - Nanoparticle composition for diagnostic imaging - Google Patents
Nanoparticle composition for diagnostic imaging Download PDFInfo
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- JP6475618B2 JP6475618B2 JP2015527909A JP2015527909A JP6475618B2 JP 6475618 B2 JP6475618 B2 JP 6475618B2 JP 2015527909 A JP2015527909 A JP 2015527909A JP 2015527909 A JP2015527909 A JP 2015527909A JP 6475618 B2 JP6475618 B2 JP 6475618B2
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- metal oxide
- nanoparticle composition
- hydrogen
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- 239000002105 nanoparticle Substances 0.000 title claims description 136
- 239000000203 mixture Substances 0.000 title claims description 87
- 238000002059 diagnostic imaging Methods 0.000 title claims description 24
- -1 bromine ions Chemical class 0.000 claims description 62
- 229910044991 metal oxide Inorganic materials 0.000 claims description 48
- 150000004706 metal oxides Chemical class 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- BPUBBGLMJRNUCC-UHFFFAOYSA-N oxygen(2-);tantalum(5+) Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[Ta+5].[Ta+5] BPUBBGLMJRNUCC-UHFFFAOYSA-N 0.000 claims description 27
- 239000003446 ligand Substances 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 229910001936 tantalum oxide Inorganic materials 0.000 claims description 23
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 21
- 125000002723 alicyclic group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 239000012216 imaging agent Substances 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 13
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 12
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 1
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- 125000001188 haloalkyl group Chemical group 0.000 description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
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- 229910052711 selenium Inorganic materials 0.000 description 3
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- 239000011593 sulfur Chemical group 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NGCRLFIYVFOUMZ-UHFFFAOYSA-N 2,3-dichloroquinoxaline-6-carbonyl chloride Chemical compound N1=C(Cl)C(Cl)=NC2=CC(C(=O)Cl)=CC=C21 NGCRLFIYVFOUMZ-UHFFFAOYSA-N 0.000 description 2
- WBUSESIMOZDSHU-UHFFFAOYSA-N 3-(4,5-dihydroimidazol-1-yl)propyl-triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN1CCN=C1 WBUSESIMOZDSHU-UHFFFAOYSA-N 0.000 description 2
- HTSABYAWKQAHBT-UHFFFAOYSA-N 3-methylcyclohexanol Chemical compound CC1CCCC(O)C1 HTSABYAWKQAHBT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
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- JHJNPOSPVGRIAN-SFHVURJKSA-N n-[3-[(1s)-1-[[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino]ethyl]phenyl]-5-methylpyridine-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN=CC(N[C@@H](C)C=2C=C(NC(=O)C=3C=C(C)C=NC=3)C=CC=2)=N1 JHJNPOSPVGRIAN-SFHVURJKSA-N 0.000 description 2
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- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100001251 short-term toxicity Toxicity 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005369 trialkoxysilyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
- A61K49/0423—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
- A61K49/0428—Surface-modified nanoparticles, e.g. immuno-nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
- A61K49/1848—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a silane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Description
本出願は、概してＸ線／コンピュータ断層撮影（ＣＴ）及び磁気共鳴画像法（ＭＲＩ）の１以上に使用するための画像診断薬として有用なナノ粒子組成物に関する。より具体的には、本出願は、造影剤として有用なナノ粒子組成物、並びに造影剤の製造及び使用方法に関する。 This application relates generally to nanoparticle compositions useful as diagnostic imaging agents for use in one or more of X-ray / computed tomography (CT) and magnetic resonance imaging (MRI). More specifically, this application relates to nanoparticle compositions useful as contrast agents and methods for making and using contrast agents.
ほとんど全ての臨床的に承認されている診断用造影剤は、低分子を含む組成物である。Ｘ線及びＣＴでは比較的小型のヨウ素化された芳香族化合物が標準的な造影剤として働いているが、磁気共鳴画像法にはＧｄキレートが使用されている。公知の造影剤は、過度に速い体内からのクリアランス、過度に長い体内での滞留、毒性、非特異性、不安定性及び高いコストなどの１以上の欠点に悩まされている。かかる制限が画像診断に頼る治療プログラムの全体的な有効性を低減するよう作用している。現在までにこの分野で相当な進歩がなされたにもかかわらず、これらの欠点の１以上を克服する、及び／又は新たな様式の画像診断を可能にする特性を有する新規なクラスの造影剤が依然として必要とされている。 Almost all clinically approved diagnostic contrast agents are compositions containing small molecules. In X-ray and CT, relatively small iodinated aromatic compounds serve as standard contrast agents, but Gd chelates are used for magnetic resonance imaging. Known contrast agents suffer from one or more drawbacks such as excessively fast clearance from the body, excessively long body residence, toxicity, non-specificity, instability and high cost. Such limitations serve to reduce the overall effectiveness of treatment programs that rely on diagnostic imaging. Despite considerable progress in the field to date, there is a new class of contrast agents that have properties that overcome one or more of these drawbacks and / or enable new forms of imaging. There is still a need.
ナノ粒子組成物は、診断と治療の両方の医学的用途で相当な有望性を示している。わずか数種のナノ粒子組成物含有薬剤しか磁気共鳴画像法用途及び薬剤送達用途のために臨床的に承認されていないが、数百のかかる薬剤がまだ開発中である。診断及び治療の有効性の点でナノ粒子組成物が現在使用されている低分子薬剤に対して利点を有するという実質的証拠が存在する。しかし、ナノ粒子組成物に基づく薬剤のインビボ生体分布及びクリアランスに対する粒径、構造及び表面特性の影響は十分には理解されていない。ナノ粒子は、そのサイズに応じて、低分子に比べて長期間体内にとどまる傾向がある。造影剤の場合、最小の短期又は長期毒性と共に最大の体内からの薬剤の腎クリアランスを有することが好ましい。 Nanoparticle compositions have shown considerable promise in both diagnostic and therapeutic medical applications. While only a few nanoparticle composition-containing drugs have been clinically approved for magnetic resonance imaging and drug delivery applications, hundreds of such drugs are still in development. There is substantial evidence that nanoparticle compositions have advantages over currently used small molecule drugs in terms of diagnostic and therapeutic efficacy. However, the effects of particle size, structure and surface properties on in vivo biodistribution and clearance of drugs based on nanoparticle compositions are not well understood. Depending on their size, nanoparticles tend to stay in the body for longer periods of time compared to small molecules. In the case of contrast agents, it is preferable to have maximum renal clearance of the drug from the body with minimal short-term or long-term toxicity.
したがって、改善された特性を有し、造影剤及び／又はイメージング剤として使用するための新規なナノ粒子組成物が必要とされている。特に、腎クリアランス及び毒性に関して改善された特性を有するナノ粒子組成物があれば特に有用である。さらに、かかるナノ粒子組成物を調製するための新規な合成中間体が必要とされている。 Accordingly, there is a need for new nanoparticle compositions having improved properties and for use as contrast agents and / or imaging agents. In particular, nanoparticle compositions having improved properties with respect to renal clearance and toxicity are particularly useful. Furthermore, there is a need for new synthetic intermediates for preparing such nanoparticle compositions.
第１の態様では、本発明は、構造Ｉのトリアルコキシシランを提供する。 In a first aspect, the present invention provides a trialkoxysilane of structure I.
第２の態様では、本発明は、理想構造ＩＩを有するナノ粒子を含むナノ粒子組成物であって、ナノ粒子が官能化ナノ粒子状金属酸化物と正荷電トリオキシシランリガンドとを含んでいる、ナノ粒子組成物を提供する。 In a second aspect, the present invention is a nanoparticle composition comprising nanoparticles having ideal structure II, wherein the nanoparticles comprise a functionalized nanoparticulate metal oxide and a positively charged trioxysilane ligand. A nanoparticle composition is provided.
第３の態様では、本発明は、理想構造ＩＩＩを有するナノ粒子を含むナノ粒子組成物であって、ナノ粒子が官能化ナノ粒子状金属酸化物とトリオキシシランベタインリガンドとを含んでいる、ナノ粒子組成物を提供する。 In a third aspect, the invention is a nanoparticle composition comprising nanoparticles having an ideal structure III, wherein the nanoparticles comprise a functionalized nanoparticulate metal oxide and a trioxysilane betaine ligand. A nanoparticle composition is provided.
さらに第４の態様では、本発明は、理想構造ＩＩＩを有するナノ粒子を含む画像診断薬組成物であって、ナノ粒子が官能化ナノ粒子状金属酸化物とトリオキシシランベタインリガンドとを含んでいる、画像診断薬組成物を提供する。 In a fourth aspect, the present invention provides a diagnostic imaging agent composition comprising a nanoparticle having ideal structure III, wherein the nanoparticle comprises a functionalized nanoparticulate metal oxide and a trioxysilane betaine ligand. A diagnostic imaging agent composition is provided.
本明細書及び特許請求の範囲では多くの用語を用いるが、これらは以下の意味をもつものと定義される。 A number of terms are used throughout the specification and claims, which are defined to have the following meanings:
単数形で記載したものであっても、前後関係から明らかでない限り、複数の場合も含めて意味する。 Even in the singular form, it includes plural cases unless it is clear from the context.
「任意の」又は「任意には」という用語は、その用語に続いて記載された事象又は状況が起きても起きなくてもよいことを意味しており、かかる記載はその事象が起こる場合と起こらない場合を包含する。 The term “optional” or “optionally” means that the event or situation described following the term may or may not occur, and such a description may be used when the event occurs. Includes cases that do not occur.
本明細書及び特許請求の範囲で用いる近似表現は、数量を修飾し、その数量が関係する基本機能に変化をもたらさない許容範囲内で変動し得る数量を表現する際に適用される。したがって、「約」及び「実質的に」のような用語で修飾された値はその厳密な数値に限定されない。場合によっては、近似表現は、その値を測定する機器の精度に対応する。本明細書及び特許請求の範囲において、数値限定の範囲は互いに結合及び／又は交換可能であり、かかる範囲はその上下限で規定され、前後関係等から明らかでない限り、その範囲に含まれるあらゆる部分範囲を包含する。 Approximate expressions used in the specification and claims apply in modifying quantities and representing quantities that can vary within an acceptable range that does not change the underlying function involved. Thus, values modified with terms such as “about” and “substantially” are not limited to the exact numerical values. In some cases, the approximate representation corresponds to the accuracy of the instrument that measures the value. In the present specification and claims, the ranges of numerical limitations are mutually connectable and / or interchangeable, and such ranges are defined by the upper and lower limits thereof, and unless otherwise clear from the context, etc. Includes a range.
本明細書で用いる「芳香族基」という用語は、１以上の芳香族基を含む原子価１以上の原子配列をいう。１以上の芳香族基を含む原子価１以上の原子配列は、窒素、硫黄、セレン、ケイ素及び酸素のようなヘテロ原子を含んでいてもよいし、炭素と水素のみからなるものでもよい。本明細書で用いる「芳香族基」という用語には、特に限定されないが、
フェニル基、ピリジル基、フラニル基、チエニル基、ナフチル基、フェニレン基及びビフェニル基が包含される。上述の通り、芳香族基は１以上の芳香族基を含む。芳香族基は常に４ｎ＋２（式中、「ｎ」は１以上の整数である。）の「非局在化」電子を有する環状構造であり、フェニル基（ｎ＝１）、チエニル基（ｎ＝１）、フラニル基（ｎ＝１）、ナフチル基（ｎ＝２）、アズレニル基（ｎ＝２）、アントラセニル基（ｎ＝３）などで例示される。芳香族基は非芳香族成分を含んでいてもよい。例えば、ベンジル基はフェニル環（芳香族基）とメチレン基（非芳香族成分）とを含む芳香族基である。同様に、テトラヒドロナフチル基は芳香族基（Ｃ6Ｈ3）が非芳香族成分−（ＣＨ2）4−と縮合してなる芳香族基である。
便宜上、「芳香族基」という用語は、本明細書では、アルキル基、アルケニル基、アルキニル基、ハロアルキル基、ハロ芳香族基、共役ジエニル基、アルコール基、エーテル基、アルデヒド基、ケトン基、カルボン酸基、アシル基（例えば、エステルやアミドのようなカルボン酸誘導体）、アミン基、ニトロ基などの広範な官能基を含むものと定義される。例えば、４−メチルフェニル基はメチル基を含むＣ7芳香族基であり、メチル基がアルキル基である官能基である。同様に、２−ニトロフェニル基はニトロ基を含むＣ6芳香族基であり、ニトロ基が官能基である。芳香族基は、４−トリフルオロメチルフェニル、ヘキサフルオロイソプロピリデンビス（４−フェン−１−イルオキシ）（即ち、−ＯＰｈＣ（ＣＦ3）2ＰｈＯ−）、４−クロロメチルフェン−１−イル、３−トリフルオロビニル−２−チエニル、３−トリクロロメチルフェン−１−イル（即ち、３−ＣＣｌ3Ｐｈ−）、４−（３−ブロモプロプ−１−イル）フェン−１−イル（即ち、４−ＢｒＣＨ2ＣＨ2ＣＨ2Ｐｈ−）などのハロゲン化芳香族基を包含する。芳香族基のその他の例には、４−アリルオキシフェン−１−オキシ、４−アミノフェン−１−イル（即ち、４−Ｈ2ＮＰｈ−）、３−アミノカルボニルフェン−１−イル（即ち、ＮＨ2ＣＯＰｈ−）、４−ベンゾイルフェン−１−イル、ジシアノメチリデンビス（４−フェン−１−イルオキシ）（即ち、−ＯＰｈＣ（ＣＮ）2ＰｈＯ−）、３−メチルフェン−１−イル、メチレンビス（４−フェン−１−イルオキシ）（即ち、−ＯＰｈＣＨ2ＰｈＯ−）、２−エチルフェン−１−イル、フェニルエテニル、３−ホルミル−２−チエニル、２−ヘキシル−５−フラニル、ヘキサメチレン−１，６−ビス（４−フェン−１−イルオキシ）（即ち、−ＯＰｈ（ＣＨ2）6ＰｈＯ−）、４−ヒドロキシメチルフェン−１−イル（即ち、４−ＨＯＣＨ2Ｐｈ−）、４−メルカプトメチルフェン−１−イル（即ち、４−ＨＳＣＨ2Ｐｈ−）、４−メチルチオフェン−１−イル（即ち、４−ＣＨ3ＳＰｈ−）、３−メトキシフェン−１−イル、２−メトキシカルボニルフェン−１−イルオキシ（例えば、メチルサリチル）、２−ニトロメチルフェン−１−イル（即ち、２−ＮＯ2ＣＨ2Ｐｈ）、３−トリメチルシリルフェン−１−イル、４−ｔ−ブチルジメチルシリルフェン−１−イル、４−ビニルフェン−１−イル、ビニリデンビス（フェニル）などがある。「Ｃ3〜Ｃ10芳香族基」という用語は、炭素原子数が３以上で１０以下の芳香族基を包含する。芳香族基１−イミダゾリル（Ｃ3Ｈ2Ｎ2−）はＣ3芳香族基の代表例である。ベンジル基（Ｃ7Ｈ8−）はＣ7芳香族基の代表例である。
As used herein, the term “aromatic group” refers to an atomic arrangement of one or more valences that includes one or more aromatic groups. The atomic arrangement of one or more valences containing one or more aromatic groups may contain heteroatoms such as nitrogen, sulfur, selenium, silicon and oxygen, or may consist of only carbon and hydrogen. The term “aromatic group” as used herein is not particularly limited,
Phenyl, pyridyl, furanyl, thienyl, naphthyl, phenylene and biphenyl groups are included. As described above, the aromatic group includes one or more aromatic groups. The aromatic group is always a cyclic structure having 4n + 2 (where “n” is an integer of 1 or more) “delocalized” electrons, and includes a phenyl group (n = 1), a thienyl group (n = 1), furanyl group (n = 1), naphthyl group (n = 2), azulenyl group (n = 2), anthracenyl group (n = 3) and the like. The aromatic group may contain a non-aromatic component. For example, a benzyl group is an aromatic group that includes a phenyl ring (aromatic group) and a methylene group (non-aromatic component). Similarly, a tetrahydronaphthyl group is an aromatic group formed by condensing an aromatic group (C 6 H 3 ) with a non-aromatic component — (CH 2 ) 4 —.
For convenience, the term “aromatic group” is used herein to refer to alkyl, alkenyl, alkynyl, haloalkyl, haloaromatic, conjugated dienyl, alcohol, ether, aldehyde, ketone, It is defined to include a wide range of functional groups such as acid groups, acyl groups (for example, carboxylic acid derivatives such as esters and amides), amine groups, and nitro groups. For example, the 4-methylphenyl radical is a C 7 aromatic radical comprising a methyl group, the methyl group being a functional group which is an alkyl group. Similarly, the 2-nitrophenyl group is a C 6 aromatic group containing a nitro group, and the nitro group is a functional group. Aromatic groups include 4-trifluoromethylphenyl, hexafluoroisopropylidenebis (4-phen-1-yloxy) (ie —OPhC (CF 3 ) 2 PhO—), 4-chloromethylphen-1-yl, trifluorovinyl-2-thienyl, 3-trichloromethylphen-1-yl (i.e., 3-CCl 3 Ph -) , 4- (3- bromoprop-1-yl) phen-1-yl (i.e., 4 A halogenated aromatic group such as —BrCH 2 CH 2 CH 2 Ph—). Other examples of aromatic groups include 4-allyloxyphen-1-oxy, 4-aminophen-1-yl (ie 4-H 2 NPh-), 3-aminocarbonylphen-1-yl (ie , NH 2 COPh -), 4-benzoyl 1-yl, dicyanomethylidene bis (4-phen-1-yloxy) (i.e., -OPhC (CN) 2 PhO - ), 3- methyl-1-yl , methylenebis (4-phen-1-yloxy) (i.e., -OPhCH 2 PhO -), 2- Echirufen-1-yl, phenylethenyl, 3-formyl-2-thienyl, 2-hexyl-5-furanyl, hexamethylene methylene-1,6-bis (4-phen-1-yloxy) (i.e., -OPh (CH 2) 6 PhO -), 4- hydroxymethyl-1-yl (i.e., 4-HOCH 2 h -), 4-mercaptomethyl-1-yl (i.e., 4-HSCH 2 Ph -) , 4- methyl-thiophen-1-yl (i.e., 4-CH 3 SPh -) , 3- methoxy-phen-1 Yl, 2-methoxycarbonylphen-1-yloxy (eg methyl salicyl), 2-nitromethylphen-1-yl (ie 2-NO 2 CH 2 Ph), 3-trimethylsilylphen-1-yl, 4- Examples include t-butyldimethylsilylphen-1-yl, 4-vinylphen-1-yl, vinylidenebis (phenyl), and the like. The term “C 3 -C 10 aromatic group” includes aromatic groups having 3 to 10 carbon atoms. The aromatic group 1-imidazolyl (C 3 H 2 N 2 —) is a representative example of a C 3 aromatic group. A benzyl group (C 7 H 8 —) is a representative example of a C 7 aromatic group.
本明細書で用いる「脂環式基」という用語は、環状であるが芳香族でない原子配列を含む原子価１以上の基をいう。本明細書で定義される「脂環式基」は、芳香族原子団を含まない。「脂環式基」は１以上の非環式成分を含んでいてもよい。例えば、シクロヘキシルメチル基（Ｃ6Ｈ11ＣＨ2−）は、シクロヘキシル環（環状であるが芳香族でない原子配列）とメチレン基（非環式成分）とを含む脂環式基である。脂環式基は、窒素、硫黄、セレン、ケイ素及び酸素のようなヘテロ原子を含んでいてもよいし、炭素と水素のみからなるものでもよい。便宜上、「脂環式基」という用語は、本明細書では、アルキル基、アルケニル基、アルキニル基、ハロアルキル基、共役ジエニル基、アルコール基、エーテル基、アルデヒド基、ケトン基、カルボン酸基、アシル基（例えば、エステルやアミドのようなカルボン酸誘導体）、アミン基、ニトロ基などの広範な官能基を含むものと定義される。例えば、４−メチルシクロペンタ−１−イル基はメチル基を含むＣ6脂環式基であり、メチル基がアルキル基である官能基である。同様に、２−ニトロシクロブタ−１−イル基はニトロ基を含むＣ4脂環式基であり、ニトロ基が官能基である。脂環式基は、同一又は異なる１以上のハロゲン原子を含んでいてもよい。ハロゲン原子には、例えば、フッ素、塩素、臭素及びヨウ素がある。１以上のハロゲン原子を含む脂環式基には、２−トリフルオロメチルシクロヘキサ−１−イル、４−ブロモジフルオロメチルシクロオクタ−１−イル、２−クロロジフルオロメチルシクロヘキサ−１−イル、ヘキサフルオロイソプロピリデン−２，２−ビス（シクロヘキサ−４−イル）（即ち、−Ｃ6Ｈ10Ｃ（ＣＦ3）2Ｃ6Ｈ10−）、２−クロロメチルシクロヘキサ−１−イル、３−ジフルオロメチレンシクロヘキサ−１−イル、４−トリクロロメチルシクロヘキサ−１−イルオキシ、４−ブロモジクロロメチルシクロヘキサ−１−イルチオ、２−ブロモエチルシクロペンタ−１−イル、２−ブロモプロピルシクロヘキサ−１−イルオキシ（例えば、ＣＨ3ＣＨＢｒＣＨ2Ｃ6Ｈ10Ｏ−）などがある。脂環式基のその他の例には、４−アリルオキシシクロヘキサ−１−イル、４−アミノシクロヘキサ−１−イル（即ち、Ｈ2ＮＣ6Ｈ10−）、４−アミノカルボニルシクロペンタ−１−イル（即ち、ＮＨ2ＣＯＣ5Ｈ8−）、４−アセチルオキシシクロヘキサ−１−イル、２，２−ジシアノイソプロピリデンビス（シクロヘキサ−４−イルオキシ）（即ち、−ＯＣ6Ｈ10Ｃ（ＣＮ）2Ｃ6Ｈ10Ｏ−）、３−メチルシクロヘキサ−１−イル、メチレンビス（シクロヘキサ−４−イルオキシ）（即ち、−ＯＣ6Ｈ10ＣＨ2Ｃ6Ｈ10Ｏ−）、１−エチルシクロブタ−１−イル、シクロプロピルエテニル、３−ホルミル−２−テトラヒドロフラニル、２−ヘキシル−５−テトラヒドロフラニル、ヘキサメチレン−１，６−ビス（シクロヘキサ−４−イルオキシ）（即ち、−ＯＣ6Ｈ10（ＣＨ2）6Ｃ6Ｈ10Ｏ−）、４−ヒドロキシメチルシクロヘキサ−１−イル（即ち、４−ＨＯＣＨ2Ｃ6Ｈ10−）、４−メルカプトメチルシクロヘキサ−１−イル（即ち、４−ＨＳＣＨ2Ｃ6Ｈ10−）、４−メチルチオシクロヘキサ−１−イル（即ち、４−ＣＨ3ＳＣ6Ｈ10−）、４−メトキシシクロヘキサ−１−イル、２−メトキシカルボニルシクロヘキサ−１−イルオキシ（２−ＣＨ3ＯＣＯＣ6Ｈ10Ｏ−）、４−ニトロメチルシクロヘキサ−１−イル（即ち、ＮＯ2ＣＨ2Ｃ6Ｈ10−）、３−トリメチルシリルシクロヘキサ−１−イル、２−ｔ−ブチルジメチルシリルシクロペンタ−１−イル、４−トリメトキシシリルエチルシクロヘキサ−１−イル（例えば、（ＣＨ3Ｏ）3ＳｉＣＨ2ＣＨ2Ｃ6Ｈ10−）、４−ビニルシクロヘキセン−１−イル、ビニリデンビス（シクロヘキシル）などがある。「Ｃ3〜Ｃ10脂環式基」という用語は、炭素原子数が３以上で１０以下の脂環式基を包含する。脂環式基２−テトラヒドロフラニル（Ｃ4Ｈ7Ｏ−）はＣ4脂環式基の代表例である。シクロヘキシルメチル基（Ｃ6Ｈ11ＣＨ2−）はＣ7脂環式基の代表例である。 As used herein, the term “alicyclic group” refers to a group having a valence of at least one comprising an atomic arrangement that is cyclic but not aromatic. An “alicyclic group” as defined herein does not contain an aromatic group. An “alicyclic group” may contain one or more acyclic components. For example, a cyclohexylmethyl group (C 6 H 11 CH 2 —) is an alicyclic group containing a cyclohexyl ring (a cyclic but non-aromatic atomic arrangement) and a methylene group (acyclic component). The alicyclic group may contain a heteroatom such as nitrogen, sulfur, selenium, silicon and oxygen, or may be composed only of carbon and hydrogen. For convenience, the term “alicyclic group” is used herein to refer to an alkyl group, alkenyl group, alkynyl group, haloalkyl group, conjugated dienyl group, alcohol group, ether group, aldehyde group, ketone group, carboxylic acid group, acyl group. Defined as containing a wide range of functional groups such as groups (eg carboxylic acid derivatives such as esters and amides), amine groups, nitro groups. For example, a 4-methylcyclopent-1-yl group is a C 6 alicyclic group containing a methyl group, and the methyl group is a functional group that is an alkyl group. Similarly, the 2-nitrocyclobut-1-yl group is a C 4 alicyclic group containing a nitro group, and the nitro group is a functional group. The alicyclic group may contain one or more halogen atoms that are the same or different. Halogen atoms include, for example, fluorine, chlorine, bromine and iodine. Alicyclic groups containing one or more halogen atoms include 2-trifluoromethylcyclohex-1-yl, 4-bromodifluoromethylcyclooct-1-yl, 2-chlorodifluoromethylcyclohex-1-yl, hexafluoro-2,2-bis (cyclohex-4-yl) (i.e., -C 6 H 10 C (CF 3) 2 C 6 H 10 -), 2- chloromethyl-cyclohexadiene-1-yl, 3 -Difluoromethylenecyclohex-1-yl, 4-trichloromethylcyclohex-1-yloxy, 4-bromodichloromethylcyclohex-1-ylthio, 2-bromoethylcyclopent-1-yl, 2-bromopropylcyclohexa 1-yloxy (e.g., O- CH 3 CHBrCH 2 C 6 H 10) , and the like. Other examples of alicyclic groups include 4-allyloxycyclohex-1-yl, 4-aminocyclohex-1-yl (ie, H 2 NC 6 H 10 —), 4-aminocarbonylcyclopenta- 1- yl (i.e., NH 2 COC 5 H 8 - ), 4- acetyloxy-cyclohexadiene-1-yl, 2,2-dicyano isopropylidene bis (cyclohex-4-yloxy) (i.e., -OC 6 H 10 C (CN) 2 C 6 H 10 O -), 3- methylcyclohexanol 1-yl, methylenebis (cyclohex-4-yloxy) (i.e., -OC 6 H 10 CH 2 C 6 H 10 O -), 1- Ethylcyclobut-1-yl, cyclopropylethenyl, 3-formyl-2-tetrahydrofuranyl, 2-hexyl-5-tetrahydrofuranyl, hexamethylene-1,6-bis (cyclohex-4- Yloxy) (i.e., -OC 6 H 10 (CH 2 ) 6 C 6 H 10 O -), 4- hydroxymethyl-cyclohexadiene-1-yl (i.e., 4-HOCH 2 C 6 H 10 -), 4- mercapto methylcyclohexanol 1-yl (i.e., 4-HSCH 2 C 6 H 10 -), 4- methylthiophenyl cyclohexadiene-1-yl (i.e., 4-CH 3 SC 6 H 10 -), 4- methoxy cyclohexanol - 1-yl, 2-methoxycarbonyl-cyclohexadiene-1-yloxy (2-CH 3 OCOC 6 H 10 O -), 4- nitro-methylcyclohexanol-1-yl (i.e., NO 2 CH 2 C 6 H 10 -) 3-trimethylsilylcyclohex-1-yl, 2-t-butyldimethylsilylcyclopent-1-yl, 4-trimethoxysilylethylcyclohex-1-yl (for example, (CH 3 O) 3 SiCH 2 CH 2 C 6 H 10 -), 4- vinylcyclohexene-1-yl, and the like vinylidene bis (cyclohexyl). The term “C 3 -C 10 alicyclic group” includes alicyclic groups having 3 to 10 carbon atoms. The alicyclic group 2-tetrahydrofuranyl (C 4 H 7 O—) is a representative example of a C 4 alicyclic group. A cyclohexylmethyl group (C 6 H 11 CH 2 —) is a representative example of a C 7 alicyclic group.
本明細書で用いる「脂肪族基」という用語は、環状でない線状又は枝分れ原子配列からなる原子価１以上の有機基をいう。脂肪族基は１以上の炭素原子を含むものと定義される。脂肪族基をなす原子配列は、窒素、硫黄、ケイ素、セレン及び酸素のようなヘテロ原子を含んでいてもよいし、炭素と水素のみからなるものでもよい。便宜上、本明細書での「脂肪族基」という用語は、「環状でない線状又は枝分れ原子配列」の一部として、アルキル基、アルケニル基、アルキニル基、ハロアルキル基、共役ジエニル基、アルコール基、エーテル基、アルデヒド基、ケトン基、カルボン酸基、アシル基（例えば、エステルやアミドのようなカルボン酸誘導体）、アミン基、ニトロ基などの広範な官能基を含むものと定義される。例えば、４−メチルペンタ−１−イル基はメチル基を含むＣ6脂肪族基であり、メチル基がアルキル基である官能基である。同様に、４−ニトロブタ−１−イル基はニトロ基を含むＣ4脂肪族基であり、ニトロ基が官能基である。脂肪族基は、同一又は異なる１以上のハロゲン原子を含むハロアルキル基であってもよい。ハロゲン原子には、例えば、フッ素、塩素、臭素及びヨウ素がある。１以上のハロゲン原子を含む脂肪族基には、ハロゲン化アルキルであるトリフルオロメチル、ブロモジフルオロメチル、クロロジフルオロメチル、ヘキサフルオロイソプロピリデン、クロロメチル、ジフルオロビニリデン、トリクロロメチル、ブロモジクロロメチル、ブロモエチル、２−ブロモトリメチレン（例えば、−ＣＨ2ＣＨＢｒＣＨ2−）などがある。脂肪族基のその他の例には、アリル、アミノカルボニル（即ち、−ＣＯＮＨ2）、カルボニル、２，２−ジシアノイソプロピリデン（即ち、−ＣＨ2Ｃ（ＣＮ）2ＣＨ2−）、メチル（即ち、−ＣＨ3）、メチレン（即ち、−ＣＨ2−）、エチル、エチレン、ホルミル（即ち、−ＣＨＯ）、ヘキシル、ヘキサメチレン、ヒドロキシメチル（即ち、−ＣＨ2ＯＨ）、メルカプトメチル（即ち、−ＣＨ2ＳＨ）、メチルチオ（即ち、−ＳＣＨ3）、メチルチオメチル（即ち、−ＣＨ2ＳＣＨ3）、メトキシ、メトキシカルボニル（即ち、ＣＨ3ＯＣＯ−）、ニトロメチル（即ち、−ＣＨ2ＮＯ2）、チオカルボニル、トリメチルシリル（即ち、（ＣＨ3）3Ｓｉ−）、ｔ−ブチルジメチルシリル、３−トリメトキシシリルプロピル（即ち、（ＣＨ3Ｏ）3ＳｉＣＨ2ＣＨ2ＣＨ2−）、ビニル、ビニリデンなどがある。その他の例としては、Ｃ1〜Ｃ10脂肪族基は炭素原子数が１以上１０以下のものである。メチル基（即ち、ＣＨ3−）はＣ1脂肪族基の例である。デシル基（即ち、ＣＨ3（ＣＨ2）9−）はＣ10脂肪族基の例である。 As used herein, the term “aliphatic group” refers to an organic group having a valence of at least one consisting of a linear or branched atom array that is not cyclic. An aliphatic group is defined as containing one or more carbon atoms. The atomic arrangement forming the aliphatic group may include heteroatoms such as nitrogen, sulfur, silicon, selenium and oxygen, or may be composed of only carbon and hydrogen. For convenience, the term “aliphatic group” as used herein refers to an alkyl group, alkenyl group, alkynyl group, haloalkyl group, conjugated dienyl group, alcohol as part of a “non-cyclic linear or branched atom array”. It is defined to include a wide range of functional groups such as groups, ether groups, aldehyde groups, ketone groups, carboxylic acid groups, acyl groups (for example, carboxylic acid derivatives such as esters and amides), amine groups, and nitro groups. For example, a 4-methylpent-1-yl group is a C 6 aliphatic group containing a methyl group, and the methyl group is a functional group that is an alkyl group. Similarly, the 4-nitrobut-1-yl group is a C 4 aliphatic group containing a nitro group, and the nitro group is a functional group. The aliphatic group may be a haloalkyl group containing one or more halogen atoms that are the same or different. Halogen atoms include, for example, fluorine, chlorine, bromine and iodine. Aliphatic groups containing one or more halogen atoms include alkyl halides trifluoromethyl, bromodifluoromethyl, chlorodifluoromethyl, hexafluoroisopropylidene, chloromethyl, difluorovinylidene, trichloromethyl, bromodichloromethyl, bromoethyl, 2-bromotrimethylene (eg, —CH 2 CHBrCH 2 —) and the like. Other examples of aliphatic groups include allyl, aminocarbonyl (ie, —CONH 2 ), carbonyl, 2,2-dicyanoisopropylidene (ie, —CH 2 C (CN) 2 CH 2 —), methyl (ie, , —CH 3 ), methylene (ie, —CH 2 —), ethyl, ethylene, formyl (ie, —CHO), hexyl, hexamethylene, hydroxymethyl (ie, —CH 2 OH), mercaptomethyl (ie, — CH 2 SH), methylthio (i.e., -SCH 3), methylthiomethyl (i.e., -CH 2 SCH 3), methoxy, methoxycarbonyl (i.e., CH 3 OCO-), nitromethyl (i.e., -CH 2 NO 2), Thiocarbonyl, trimethylsilyl (ie, (CH 3 ) 3 Si—), t-butyldimethylsilyl, 3-trimethoxysilylpropyl (ie, (CH 3 O) 3 SiCH 2 CH 2 CH 2 —), vinyl, vinylidene and the like. As another example, the C 1 -C 10 aliphatic group has 1 to 10 carbon atoms. A methyl group (ie, CH 3 —) is an example of a C 1 aliphatic group. A decyl group (ie, CH 3 (CH 2 ) 9 —) is an example of a C 10 aliphatic group.
一実施形態では、本発明は、構造Ｉのトリアルコキシシランを提供する。 In one embodiment, the present invention provides a trialkoxysilane of structure I.
トリアルコキシシランＩは、トリアルコキシシリル基の作用によってナノ粒子状金属酸化物と反応させて被覆ナノ粒子状金属酸化物を形成することができ、構造Ｉに対応するリガンドが１以上のケイ素酸素結合を通してナノ粒子状金属酸化物に結合している。 The trialkoxysilane I can react with the nanoparticulate metal oxide by the action of the trialkoxysilyl group to form a coated nanoparticulate metal oxide, and the ligand corresponding to the structure I has one or more silicon oxygen bonds To the nanoparticulate metal oxide.
構造Ｉのトリアルコキシシランを参照すると、Ｒ1は各々独立にＣ1〜Ｃ3アルキル基、例えば、メチル基、エチル基、イソプロピル基又はプロピル基である。トリアルコキシシランＩに示す２つの窒素原子は、７つの窒素−炭素結合によって５つの異なる炭素原子に結合しており、一緒に、構造Ｉの環状四級アミジニウム塩の正荷電成分を表す。構造Ｉでは、環状アミジニウム基の正電荷が単一窒素原子に局在化したものとして示したが、当業者には明らかな通り、化学理論にしたがって、正電荷が環状アミジニウム基の２つの窒素原子とそれらの間のｓｐ２炭素原子に非局在化している。全体としてみると、構造Ｉは、トリアルコキシシランと環状四級アミジニウム塩とを表す。Ｒ3基は各々独立に水素又はＣ1〜Ｃ3アルキル基である。１以上の実施形態では、各Ｒ3は水素である。Ｒ4基は温和な条件下（例えば弱酸性条件下）で除去し得る保護基であるか、或いはＲ4は温和な水素化分解条件下で除去し得る保護基である。弱酸性条件下で除去し得るエステル保護基としては、特に限定されないが、三級ブチル基、テトラヒドロピラニル基、メチルチオメチレン基、１−メチル−１−シクロペンチル基及び１−メチル−１−シクロヘキシル基が挙げられる。温和な水素化分解条件下で除去し得るエステル保護基としては、特に限定されないが、ベンジル基、ｐ−メトキシベンジル基及びｐ−アルキルベンジル基が挙げられる。 Referring to the trialkoxysilane of structure I, each R 1 is independently a C 1 -C 3 alkyl group, such as a methyl group, an ethyl group, an isopropyl group, or a propyl group. The two nitrogen atoms shown in trialkoxysilane I are bonded to five different carbon atoms by seven nitrogen-carbon bonds and together represent the positively charged component of the cyclic quaternary amidinium salt of structure I. In structure I, the positive charge of the cyclic amidinium group was shown as localized to a single nitrogen atom, but, as will be apparent to those skilled in the art, according to chemical theory, the positive charge is represented by two nitrogen atoms of the cyclic amidinium group. And delocalized in the sp2 carbon atom between them. Overall, structure I represents a trialkoxysilane and a cyclic quaternary amidinium salt. Each R 3 group is independently hydrogen or a C 1 -C 3 alkyl group. In one or more embodiments, each R 3 is hydrogen. The R 4 group is a protecting group that can be removed under mild conditions (eg, mildly acidic conditions), or R 4 is a protecting group that can be removed under mild hydrogenolysis conditions. The ester protecting group that can be removed under weakly acidic conditions is not particularly limited, but is a tertiary butyl group, a tetrahydropyranyl group, a methylthiomethylene group, a 1-methyl-1-cyclopentyl group, and a 1-methyl-1-cyclohexyl group. Is mentioned. Ester protecting groups that can be removed under mild hydrocracking conditions include, but are not limited to, benzyl, p-methoxybenzyl and p-alkylbenzyl groups.
構造Ｉのトリアルコキシシラン化合物は、以下の表Ｉの例１ａ〜１ｏで例示される。本明細書の記載から、かかる化合物をどのように調製できるかは当業者には明らかであろう。例えば、反応性脱離基を含む保護エステル化合物を、三級環状アミジン基（即ち、２つの窒素原子が、それらを隔てるｓｐ２炭素原子を含めた４つの異なる炭素原子に窒素−炭素結合で結合しているアミジン基）を含むトリアルコキシシランと反応させることができる。アミジン基の立体障害性の低い方の窒素原子が、反応性脱離基を含む保護エステル化合物と反応して、三級環状アミジン基が四級環状アミジニウム基へと変換される。化合物１ａ〜１ｄ、１ｉ〜１ｋ及び１ｍ〜１ｏは、本発明で提供するトリアルコキシシランであって、Ｒ4基が酸感受性保護基であるものを例示している。化合物１ｅ〜１ｈ及び１ｌは、本発明で提供するトリアルコキシシランであって、Ｒ4基が温和な水素化分解条件下（例えば、炭素に担持したパラジウムの存在下で周囲圧力、周囲温度条件下での水素ガスへの暴露）で除去し得る保護基（ベンジル）であるものを例示している。なお、水素化分解条件下で除去し得る他の保護基（例えばｐ−メチルベンジル基、ｐ−ブロモベンジル基及びｐ−フルオロベンジル基）も好適である。 The trialkoxysilane compounds of structure I are illustrated in Examples 1a-1o of Table I below. It will be apparent to those skilled in the art from the description herein how such compounds can be prepared. For example, a protected ester compound containing a reactive leaving group can be linked to a tertiary cyclic amidine group (ie, two nitrogen atoms bonded to four different carbon atoms, including the sp2 carbon atom separating them, via a nitrogen-carbon bond). Can be reacted with a trialkoxysilane containing an amidine group). The nitrogen atom having the lower steric hindrance of the amidine group reacts with a protected ester compound containing a reactive leaving group, thereby converting the tertiary cyclic amidine group into a quaternary cyclic amidinium group. Compounds 1a to 1d, 1i to 1k, and 1m to 1o are trialkoxysilanes provided in the present invention and exemplify those in which the R 4 group is an acid-sensitive protecting group. Compounds 1e to 1h and 1l are trialkoxysilanes provided in the present invention, wherein R 4 group is mildly hydrocracked under conditions (for example, ambient pressure in the presence of palladium on carbon, ambient temperature conditions). Exemplified is a protecting group (benzyl) that can be removed by exposure to hydrogen gas at Other protecting groups that can be removed under hydrogenolysis conditions (for example, p-methylbenzyl group, p-bromobenzyl group and p-fluorobenzyl group) are also suitable.
表１では、構造Ｉの電荷均衡用対イオンＸ-が、臭素（Ｂｒ-）、ヨウ素（Ｉ-）、トシレート（ＴｓＯ-）、メシレート（ＭｓＯ-）、酢酸（ＡｃＯ-）、炭酸水素（ＨＣＯ3-）及びトリフルオロメタンスルホネート（Ｔｆ-）で例示されているが、有機及び無機アニオンのホストも同様に適している。 In Table 1, the charge balance counter ion X − of structure I is bromine (Br − ), iodine (I − ), tosylate (TsO − ), mesylate (MsO − ), acetic acid (AcO − ), hydrogen carbonate (HCO). 3- ) and trifluoromethanesulfonate (Tf − ), but organic and inorganic anion hosts are equally suitable.
１以上の別の実施形態では、本発明は、一般構造Ｉの範囲に属するトリアルコキシシランであって、各Ｒ1がエチルであり、各Ｒ3がメチルであり、Ｒ4が三級ブチルであるもの、例えば表Ｉの化合物１ｍを提供する。 In one or more other embodiments, the invention is a trialkoxysilane belonging to the scope of general structure I, wherein each R 1 is ethyl, each R 3 is methyl, and R 4 is tertiary butyl. Some are provided, for example, compounds 1m of Table I.
１以上の追加の実施形態では、本発明は、一般構造Ｉの範囲に属するトリアルコキシシランであって、各Ｒ1がメチルであり、各Ｒ3が水素であり、Ｒ4が２−メチル−２−ブチルであるもの、例えば表Ｉの化合物１ｏを提供する。 In one or more additional embodiments, the present invention relates to trialkoxysilanes belonging to the scope of general structure I, wherein each R 1 is methyl, each R 3 is hydrogen, and R 4 is 2-methyl- Provided are those that are 2-butyl, for example compound 1o of Table I.
一実施形態では、本発明は、一般構造Ｉの範囲に属するトリアルコキシシランであって、Ｒ4がベンジルであるもの、例えば表Ｉの化合物１ｅ〜１ｈ及び１ｌを提供する。別の実施形態では、Ｒ4はｐ−メトキシベンジルである。 In one embodiment, the present invention provides trialkoxysilanes belonging to the scope of general structure I wherein R 4 is benzyl, for example compounds 1e-1h and 1l of Table I. In another embodiment, R 4 is p-methoxybenzyl.
上述の通り、トリアルコキシシランＩは、それ自体で医用画像診断における造影剤として有用なナノ粒子の調製に有用である。トリアルコキシシランＩに存在するトリアルコキシシラン基（Ｒ1Ｏ）3Ｓｉをナノ粒子状酸化タンタルのようなナノ粒子状金属酸化物の反応性酸素含有基と縮合させて、ナノ粒子状金属酸化物の表面を被覆して、官能化ナノ粒子状金属酸化物と正荷電トリオキシシランリガンドとを含むナノ粒子組成物を得ることができる。かかる官能化ナノ粒子状金属酸化物の構造は複雑であり、ナノ粒子状金属酸化物粒子に結合した複数のトリオキシシランリガンドを含むことがある。「官能化」という用語は、本発明に関しては、「被覆」又は「部分的被覆」を意味するものと解釈することができ、ナノ粒子状金属酸化物を「被覆する」トリオキシシランリガンドの少なくとも一部は実際に１以上の酸素ケイ素結合を介してナノ粒子状金属酸化物に化学結合している。 As described above, trialkoxysilane I is useful by itself for the preparation of nanoparticles that are useful as contrast agents in medical diagnostic imaging. Trialkoxysilane group (R 1 O) 3 Si present in trialkoxysilane I is condensed with a reactive oxygen-containing group of a nanoparticulate metal oxide such as nanoparticulate tantalum oxide to form a nanoparticulate metal oxide To obtain a nanoparticle composition comprising a functionalized nanoparticulate metal oxide and a positively charged trioxysilane ligand. The structure of such functionalized nanoparticulate metal oxides is complex and may include multiple trioxysilane ligands bound to the nanoparticulate metal oxide particles. The term “functionalization” in the context of the present invention can be taken to mean “coating” or “partial coating”, and at least of the trioxysilane ligands “coating” the nanoparticulate metal oxide. Some are actually chemically bonded to the nanoparticulate metal oxide via one or more oxygen silicon bonds.
特定の状況下では、本発明で提供するトリアルコキシシランＩに対応するトリオキシシランリガンドを含むナノ粒子は、次の三級アミジン基を含むトリアルコキシシランＩａに対応するトリオキシシランリガンドをさらに含んでいてもよい。 Under certain circumstances, the nanoparticle comprising a trioxysilane ligand corresponding to trialkoxysilane I provided in the present invention further comprises a trioxysilane ligand corresponding to trialkoxysilane Ia containing the following tertiary amidine group. You may go out.
ナノ粒子における三級アミジンＩａに対応するかかるトリオキシシランリガンドの存在は、かかるナノ粒子の画像診断薬としての性能特性に影響するとともに、かかるナノ粒子の毒性特性にも影響することがある。特定の実施形態では、本発明で提供するナノ粒子は、トリアルコキシシランＩに対応するトリオキシシランリガンドとトリアルコキシシランＩａに対応するトリオキシシランリガンドを共に含む。一実施形態では、本発明で提供するナノ粒子に存在するトリオキシシランリガンドの５０％未満がトリアルコキシシランＩａに対応する。別の実施形態では、本発明で提供するナノ粒子に存在するトリオキシシランリガンドの２０％未満がトリアルコキシシランＩａに対応する。さらに別の実施形態では、本発明で提供するナノ粒子に存在するトリオキシシランリガンドの５％未満がトリアルコキシシランＩａに対応する。別の実施形態では、本発明で提供するナノ粒子はトリアルコキシシランＩａに対応するトリオキシシランリガンドを実質的に含まない。 The presence of such trioxysilane ligands corresponding to tertiary amidine Ia in the nanoparticles affects the performance characteristics of such nanoparticles as diagnostic imaging agents and may also affect the toxicity characteristics of such nanoparticles. In a particular embodiment, the nanoparticles provided in the present invention comprise both a trioxysilane ligand corresponding to trialkoxysilane I and a trioxysilane ligand corresponding to trialkoxysilane Ia. In one embodiment, less than 50% of the trioxysilane ligands present in the nanoparticles provided herein correspond to trialkoxysilane Ia. In another embodiment, less than 20% of the trioxysilane ligand present in the nanoparticles provided herein corresponds to trialkoxysilane Ia. In yet another embodiment, less than 5% of the trioxysilane ligands present in the nanoparticles provided herein correspond to trialkoxysilane Ia. In another embodiment, the nanoparticles provided in the present invention are substantially free of a trioxysilane ligand corresponding to trialkoxysilane Ia.
便宜上、官能化ナノ粒子組成物を、ナノ粒子状金属酸化物に略同じ大きさの１個のトリオキシシランリガンドが結合したものを表す球体として示すことが多い。実際には、ナノ粒子状金属酸化物粒子は、組成物中の各ナノ粒子状金属酸化物粒子に結合した複数のトリオキシシランリガンドよりもかなり大きい。さらに、トリアルコキシシランＩはナノ粒子状金属酸化物の反応性酸素含有基と縮合するので、複数の縮合経路が可能である。ナノ粒子組成物を化学的に表現するに当たってこのようにかなり理想化してはいるが、本発明で提供するナノ粒子組成物の性状及び化学構造並びにこれらの構造が公知のナノ粒子組成物と如何に異なっているかは当業者には明らかであろう。ナノ粒子組成物の化学構造を１以上の観点で単純化したとき、それを本明細書では理想構造を有するという。 For convenience, the functionalized nanoparticle composition is often shown as a sphere representing a nanoparticulate metal oxide bound to a single trioxysilane ligand of approximately the same size. In practice, the nanoparticulate metal oxide particles are significantly larger than the plurality of trioxysilane ligands attached to each nanoparticulate metal oxide particle in the composition. Furthermore, trialkoxysilane I condenses with the reactive oxygen-containing groups of the nanoparticulate metal oxide, so that multiple condensation paths are possible. Although it is quite idealized in the chemical expression of the nanoparticle composition, the properties and chemical structure of the nanoparticle composition provided in the present invention and how these structures are different from those of known nanoparticle compositions. It will be apparent to those skilled in the art whether they are different. When the chemical structure of a nanoparticle composition is simplified in one or more respects, it is referred to herein as having an ideal structure.
一実施形態では、本発明は、理想構造ＩＩを有するナノ粒子を含むナノ粒子組成物であって、ナノ粒子が官能化ナノ粒子状金属酸化物と正荷電トリオキシシランリガンドとを含んでいる、ナノ粒子組成物を提供する。 In one embodiment, the invention is a nanoparticle composition comprising nanoparticles having ideal structure II, wherein the nanoparticles comprise a functionalized nanoparticulate metal oxide and a positively charged trioxysilane ligand. A nanoparticle composition is provided.
本発明で提供するナノ粒子組成物の各々は、酸化タンタル（Ｔａ2Ｏ5）を含むナノ粒子状金属酸化物を含む。１以上の実施形態では、酸化タンタル（Ｔａ2Ｏ5）を含むナノ粒子状金属酸化物が、Ｔａ2Ｏ5に加えて他の金属酸化物、例えば、酸化鉄及び酸化チタンを含む。ただし、典型的には、これらの追加の金属酸化物の量は、ナノ粒子状金属酸化物に存在する酸化タンタルの量に対して少ない。一実施形態では、本発明の１以上の態様で使用するナノ粒子状金属酸化物は約９０重量％の酸化タンタルである。別の実施形態では、本発明の１以上の態様で使用するナノ粒子状金属酸化物は約９５重量％の酸化タンタルである。一実施形態では、ナノ粒子状金属酸化物は酸化タンタルから実質的になり、他の金属酸化物種を１重量％未満しか含まない。 Each of the nanoparticle compositions provided by the present invention comprises a nanoparticulate metal oxide comprising tantalum oxide (Ta 2 O 5 ). In one or more embodiments, the nanoparticulate metal oxide comprising tantalum oxide (Ta 2 O 5 ) comprises other metal oxides such as iron oxide and titanium oxide in addition to Ta 2 O 5 . However, typically the amount of these additional metal oxides is small relative to the amount of tantalum oxide present in the nanoparticulate metal oxide. In one embodiment, the nanoparticulate metal oxide used in one or more aspects of the present invention is about 90% by weight tantalum oxide. In another embodiment, the nanoparticulate metal oxide used in one or more aspects of the present invention is about 95% by weight tantalum oxide. In one embodiment, the nanoparticulate metal oxide consists essentially of tantalum oxide and contains less than 1% by weight of other metal oxide species.
理想構造ＩＩを有するナノ粒子を含むナノ粒子組成物を表ＩＩに例示するが、これらは酸化タンタルを含むナノ粒子状金属酸化物と構造Ｉのトリアルコキシシラン化合物との縮合生成物に相当する。例示のため、表Ｉに記載したトリアルコキシシラン化合物の各々について、表ＩＩの官能化ナノ粒子状金属酸化物に結合した対応トリオキシシランリガンドへと変換されたものとして示す。例えば、表Ｉの構造１ａは表ＩＩの構造２ａに対応し、表Ｉの構造１ｂは表ＩＩの構造２ｂに対応する。表ＩＩに示す構造の各々は便宜上理想化されている。本明細書の記載から当業者には明らかであろうが、所与の組成物における電荷均衡用対イオンは、ナノ粒子ＩＩを含むナノ粒子組成物の調製に用いる反応プロトコルに依存する。 Nanoparticle compositions comprising nanoparticles having the ideal structure II are illustrated in Table II, which correspond to condensation products of nanoparticulate metal oxides containing tantalum oxide and a trialkoxysilane compound of structure I. For illustration, each trialkoxysilane compound listed in Table I is shown as converted to the corresponding trioxysilane ligand bound to the functionalized nanoparticulate metal oxide of Table II. For example, structure 1a in Table I corresponds to structure 2a in Table II, and structure 1b in Table I corresponds to structure 2b in Table II. Each of the structures shown in Table II is idealized for convenience. As will be apparent to those skilled in the art from the description herein, the charge balancing counterion in a given composition depends on the reaction protocol used to prepare the nanoparticle composition, including Nanoparticle II.
１以上の別の実施形態では、本発明は、一般構造ＩＩに属するナノ粒子であって、各Ｒ3が水素であり、Ｒ4が２−メチル−２−ブチルであるもの（例えば表ＩＩのナノ粒子２ｏ）を含むナノ粒子組成物を提供する。 In one or more alternative embodiments, the invention relates to nanoparticles belonging to General Structure II, wherein each R 3 is hydrogen and R 4 is 2-methyl-2-butyl (eg, in Table II Nanoparticle compositions comprising nanoparticles 2o) are provided.
一実施形態では、本発明は、一般構造ＩＩに属するナノ粒子であって、Ｒ4がベンジルであるもの（例えば表ＩＩの化合物２ｅ〜２ｈ及び２ｌ）を含むナノ粒子組成物を提供する。別の実施形態では、Ｒ4はｐ−メトキシベンジルである。 In one embodiment, the present invention provides nanoparticle compositions comprising nanoparticles belonging to general structure II, wherein R 4 is benzyl (eg, compounds 2e-2h and 2l of Table II). In another embodiment, R 4 is p-methoxybenzyl.
一実施形態では、本発明は、一般構造ＩＩに属するナノ粒子であって、各Ｒ3が水素であり、Ｒ4が三級ブチルであり、ｎが１であり、ｑが１であり、ナノ粒子状金属酸化物がナノ粒子状酸化タンタルから実質的になるものを含むナノ粒子組成物を提供する。例えば、表ＩＩの理想構造２ａのナノ粒子を参照されたい。 In one embodiment, the present invention relates to a nanoparticle belonging to General Structure II, wherein each R 3 is hydrogen, R 4 is tertiary butyl, n is 1, q is 1, Provided is a nanoparticle composition comprising a particulate metal oxide consisting essentially of nanoparticulate tantalum oxide. See, for example, nanoparticles of ideal structure 2a in Table II.
一態様では、一般構造ＩＩに属するナノ粒子を含むナノ粒子組成物は、理想構造ＩＩＩに示すトリオキシシランベタインリガンドを含むナノ粒子組成物の前駆体として特に有用である。 In one aspect, a nanoparticle composition comprising nanoparticles belonging to General Structure II is particularly useful as a precursor to a nanoparticle composition comprising a trioxysilane betaine ligand shown in Ideal Structure III.
本明細書の記載から当業者には明らかであろうが、保護基Ｒ4を含むエステル基の開裂によって、正に荷電した四級アミジニウム基に対する電荷均衡用対イオンとして作用できるカルボキシレート基が得られる。このように電荷が分離しているが、電荷が釣り合っている化学種は有機化学ではベタインと呼ばれる。 As will be apparent to those skilled in the art from the description herein, cleavage of the ester group containing the protecting group R 4 yields a carboxylate group that can act as a charge balancing counterion for a positively charged quaternary amidinium group. It is done. Although the charges are separated in this way, the chemical species in which the charges are balanced is called betaine in organic chemistry.
表ＩＩＩに、一般構造ＩＩＩに属するナノ粒子を含むナノ粒子組成物であって、官能化ナノ粒子状金属酸化物とトリオキシシランベタインリガンドとを含むものの具体例を示す。 Table III shows specific examples of nanoparticle compositions containing nanoparticles belonging to General Structure III, which contain functionalized nanoparticulate metal oxides and trioxysilane betaine ligands.
１以上の別の実施形態では、本発明は、一般構造ＩＩＩに属するナノ粒子であって、各Ｒ3がメチルであるもの（例えば、表ＩＩＩの構造３ｍで表されるナノ粒子）を含むナノ粒子組成物を提供する。 In one or more alternative embodiments, the invention includes nanoparticles comprising nanoparticles belonging to general structure III, wherein each R 3 is methyl (eg, a nanoparticle represented by structure 3m in Table III). A particle composition is provided.
１以上の別の実施形態では、本発明は、一般構造ＩＩＩに属するナノ粒子であって、ｎが１であり、ｑが１であり、官能化ナノ粒子状金属酸化物が酸化タンタルから実質的になるもの（例えば、表ＩＩＩの構造３ａ〜３ｅ及び３ｌ〜３ｍで表されるナノ粒子）を含むナノ粒子組成物を提供する。 In one or more alternative embodiments, the present invention relates to nanoparticles belonging to general structure III, wherein n is 1, q is 1, and the functionalized nanoparticulate metal oxide is substantially from tantalum oxide. Provided are nanoparticle compositions comprising (eg, nanoparticles represented by structures 3a-3e and 3l-3m of Table III).
さらに別の態様では、本発明は、理想構造ＩＩＩを有するナノ粒子を含む画像診断薬組成物を提供する。１以上の実施形態では、画像診断薬組成物は薬学的に許容される担体及び／又は賦形剤を含んでいてもよい。薬学的に許容される担体として適したものには、特に限定されないが、水及び水性エタノールが挙げられる。薬学的に許容される賦形剤として適したものには、特に限定されないが、塩、崩壊剤、結合剤、充填剤、潤滑剤及びこれらの２種以上の組合せが挙げられる。 In yet another aspect, the present invention provides a diagnostic imaging composition comprising nanoparticles having ideal structure III. In one or more embodiments, the diagnostic imaging composition may include a pharmaceutically acceptable carrier and / or excipient. Suitable pharmaceutically acceptable carriers include, but are not limited to, water and aqueous ethanol. Examples of suitable pharmaceutically acceptable excipients include, but are not limited to, salts, disintegrants, binders, fillers, lubricants, and combinations of two or more thereof.
本発明で提供する画像診断薬組成物の有用性の基礎をなす重要な特性は、ナノ粒子自体のナノ粒子としての性状に起因する。１以上の実施形態では、画像診断薬組成物を構成するナノ粒子は１０ｎｍ以下のメジアン粒径を有する。別の実施形態では、画像診断薬組成物を構成するナノ粒子は６ｎｍ以下のメジアン粒径を有する。 An important characteristic that forms the basis of the usefulness of the diagnostic imaging composition provided in the present invention is attributed to the properties of the nanoparticles themselves as nanoparticles. In one or more embodiments, the nanoparticles making up the diagnostic imaging agent composition have a median particle size of 10 nm or less. In another embodiment, the nanoparticles constituting the diagnostic imaging agent composition have a median particle size of 6 nm or less.
実施例１：トリアルコキシシラン３の合成Example 1: Synthesis of trialkoxysilane 3
方法１：ナノ粒子状酸化タンタル（Ｔａ 2 Ｏ 5 ）の調製
窒素充填グローブボックス中で、無水メタノール１７０ｍＬに、攪拌しながら室温で、イソ酪酸２．５ｍＬ及び重水０．６９５ｍＬを添加した。この混合物を３０分間攪拌した後、タンタルエトキシド（９．３４ｇ）を滴下した。反応混合物を５時間撹拌したところ、ナノ粒子Ｔａ2Ｏ5の溶液が得られた。フラスコをグローブボックスから取り出し、以下の実施例２に記載の手順に備えて、Ｓｃｈｌｅｎｃｋ−／真空−ラインマニホールドを用いて不活性雰囲気下に置いた。
Method 1: Preparation of Nanoparticulate Tantalum Oxide (Ta 2 O 5 ) In a nitrogen-filled glove box, 2.5 mL of isobutyric acid and 0.695 mL of heavy water were added to 170 mL of anhydrous methanol at room temperature with stirring. After stirring this mixture for 30 minutes, tantalum ethoxide (9.34 g) was added dropwise. The reaction mixture was stirred for 5 hours, resulting in a solution of nanoparticles Ta 2 O 5 . The flask was removed from the glove box and placed in an inert atmosphere using a Schlenck- / vacuum-line manifold in preparation for the procedure described in Example 2 below.
実施例２：被覆反応、ナノ粒子４の合成Example 2: Coating reaction, synthesis of nanoparticles 4
実施例３：ナノ粒子５（ＣＺ３）の合成Example 3: Synthesis of nanoparticles 5 (CZ3)
実施例４：ナノ粒子５の精製
実施例３で調製したナノ粒子５を含む溶液を、順次０．２２μｍフィルタ、次いで１００ｎｍフィルタを通して濾過した。得られた溶液を４０℃で約１００ｍＬに濃縮し、０．２２μｍフィルタを通して濾過し、次いで、３．５ｋＤａ ＭＷＣＯ再生セルロースヘビ皮透析チューブを用いて透析して低分子量不純物を除去した。透析槽は約３Ｌの体積を有し、それぞれナノ粒子５を含む溶液５０ｍＬを含む２本のチューブを含んでいた。合計７回の槽交換後、生成物含有溶液をチューブから取り出し、１００ｎｍ濾過によってさらに精製すると、ナノ粒子５を含む生成ナノ粒子組成物の精製溶液が得られた。一定分量を凍結乾燥し、分光学的に分析した。生成物収率は７０％であり、これは精製された生成溶液に存在するタンタルの量に基づいた。元素分析によって決定されるように、Ｓｉ：Ｔａモル比は１．４６であることが分かった。元素分析によって決定されるように、生成物中のタンタルの重量百分率（Ｔａ％）は３３．５重量％であった。平均粒径（Ｚeff）は３．７ｎｍであることが分かった。粒子被覆構造帰属は分光学的データと一致した。
Example 4: Purification of nanoparticles 5 The solution containing nanoparticles 5 prepared in Example 3 was sequentially filtered through a 0.22 μm filter and then a 100 nm filter. The resulting solution was concentrated to approximately 100 mL at 40 ° C., filtered through a 0.22 μm filter, and then dialyzed using a 3.5 kDa MWCO regenerated cellulose snake skin dialysis tube to remove low molecular weight impurities. The dialysis tank had a volume of about 3 L and contained two tubes each containing 50 mL of solution containing nanoparticles 5. After a total of seven tank exchanges, the product-containing solution was removed from the tube and further purified by 100 nm filtration to obtain a purified solution of the resulting nanoparticle composition containing nanoparticles 5. Aliquots were lyophilized and analyzed spectroscopically. The product yield was 70%, which was based on the amount of tantalum present in the purified product solution. As determined by elemental analysis, the Si: Ta molar ratio was found to be 1.46. As determined by elemental analysis, the weight percentage (Ta%) of tantalum in the product was 33.5% by weight. The average particle size (Z eff ) was found to be 3.7 nm. The particle coating structure assignment is consistent with the spectroscopic data.
方法２：ナノ粒子状酸化タンタル（Ｔａ 2 Ｏ 5 ）の代替調製
無水メタノール３６４ｍＬに、窒素充填グローブボックス中で攪拌しながら、イソ酪酸５．３６ｍＬ及び重水１．４９５ｍＬを室温で添加した。この混合物を３０分間攪拌した後、タンタルエトキシド（２０ｇ）を約８分間滴下した。反応混合物を５時間攪拌させ、その後、生成物ナノ粒子Ｔａ2Ｏ5を含むフラスコをグローブボックスから取り出し、Ｓｃｈｌｅｎｃｋ−／真空ライン−マニホールドを用いて不活性雰囲気下に置いた。
Method 2: Alternative Preparation of Nanoparticulate Tantalum Oxide (Ta 2 O 5 ) To 364 mL anhydrous methanol, 5.36 mL isobutyric acid and 1.495 mL heavy water were added at room temperature with stirring in a nitrogen filled glove box. After stirring this mixture for 30 minutes, tantalum ethoxide (20 g) was added dropwise for about 8 minutes. The reaction mixture was allowed to stir for 5 hours, after which the flask containing the product nanoparticles Ta 2 O 5 was removed from the glove box and placed under an inert atmosphere using a Schlenck- / vacuum line-manifold.
実施例５：トリアルコキシシラン７の合成Example 5: Synthesis of trialkoxysilane 7
比較例：ナノ粒子「ＣＺ１」の合成Comparative Example: Synthesis of nanoparticle “CZ1”
方法３：ナノ粒子１０（ＣＺ１）の精製
３．５ｋＤａ ＭＷＣＯチューブを用いた徹底的な透析によって、低分子量不純物を除去した。透析槽は約３Ｌの体積を有し、それぞれ生成溶液５０ｍＬ体積を含む４〜５本のチューブを含んでいた。合計２１回の槽交換後、精製した生成溶液をチューブから取り出し、３０ｋＤａ再生セルロース膜を通した遠心濾過（４Ｋｒｐｍで１５分間）によってさらに精製した。精製後の反応収率はタンタルのモル基準で５８．３％であった。Ｓｉ：Ｔａモル比は元素分析によって決定されるように１．０５であった。平均粒径（Ｚeff）は４．８ｎｍであることが分かった。粒子被覆構造帰属は分光学的データと一致する。１Ｈ−ＮＭＲ分光法でナノ粒子９に存在する三級アミン基の約５０％が対応する四級アンモニウム基に変換されたことを確認した。
Method 3: Purification of Nanoparticles 10 (CZ1) Low molecular weight impurities were removed by exhaustive dialysis using 3.5 kDa MWCO tubes. The dialysis tank had a volume of about 3 L and contained 4-5 tubes each containing a 50 mL volume of the product solution. After a total of 21 tank exchanges, the purified product solution was removed from the tube and further purified by centrifugal filtration (4K rpm for 15 minutes) through a 30 kDa regenerated cellulose membrane. The reaction yield after purification was 58.3% on a molar basis of tantalum. The Si: Ta molar ratio was 1.05 as determined by elemental analysis. The average particle size (Z eff ) was found to be 4.8 nm. The particle coating structure assignment is consistent with the spectroscopic data. It was confirmed by 1H-NMR spectroscopy that about 50% of the tertiary amine groups present in the nanoparticles 9 were converted to the corresponding quaternary ammonium groups.
実施例６：トリアルコキシシラン１２の合成Example 6: Synthesis of trialkoxysilane 12
酸化タンタルナノ粒子組成物を、注射用に製剤化し、市販のキット（Ｅｎｄｏｓａｆｅ、Ｃｈａｒｌｅｓ Ｒｉｖｅｒ Ｌａｂｓ）を用いてエンドトキシン汚染について試験した。インビボ試験に使用する全ての薬剤は、測定可能な量のエンドトキシンを含んでいなかった。試験したナノ粒子組成物の各々は、実質的に同じナノ粒径分布を有していた。
ＧＥ Ｇｌｏｂａｌ Ｒｅｓｅａｒｃｈの動物実験委員会によって承認されたプロトコルに従って動物試験を行った。ラット（薬剤及び用量当たりｎ＝４）に、覚醒している間に、体重１ｋｇ当たり４００及び１５００ｍｇのＴａの用量で尾静脈を介して注射した。注射されたラットをケージに戻し、血液学的分析（全血球算定及び臨床化学）のために注射後の複数の時点で血液試料を採取した。注射後７日で、ＣＯ2を用いてラットを安楽死させ、元素分析のために臓器を採取した。滞留Ｔａ量を、ＩＣＰ ＡＥＳによって１臓器当たり及び注射されたラットの屠殺体全体で測定した。 Animal studies were performed according to protocols approved by the Animal Research Committee of GE Global Research. Rats (n = 4 per drug and dose) were injected via the tail vein at a dose of 400 and 1500 mg Ta / kg body weight while awake. The injected rats were returned to their cages and blood samples were taken at multiple time points after injection for hematological analysis (whole blood count and clinical chemistry). Seven days after injection, rats were euthanized with CO 2 and organs were collected for elemental analysis. The amount of residual Ta was measured by ICP AES per organ and throughout the carcasses of injected rats.
重さ約５００ｍｇの組織の代表的な切片を、マイクロ波分解及びその後のＩＣＰ−ＯＥＳ分析のために回収した。試料をＶＷＲ（登録商標）無金属滅菌ポリプロピレン５０ｍＬ遠心チューブから予め洗浄した１００ｍＬ ＣＥＭ Ｃｏｒｐ ＸＰ−１５００Ｐｌｕｓ（商標）ＴＦＭ（商標）フルオロポリマーマイクロ波容器ライナーに定量的に移した。順次溶媒の添加、ボルテックス攪拌及び２ｍＬ １８ＭΩ脱イオン水（ＤＩＷ；Ｍｉｌｌｉｐｏｒｅ社（米国マサチューセッツ州ベッドフォード））、５００μＬ ＨＦ（４６．０〜５１．０％）＋１ｍＬ ＨＮＯ3（７０％）Ｕｌｔｒｅｘ（登録商標）ＩＩ超高純度試薬等級及び２ｍＬ Ｈ2Ｏ2（３０〜３２％）「Ｂａｋｅｒ Ａｎａｌｙｚｅｄ」（登録商標）Ａ．Ｃ．Ｓ．試薬等級（Ｊ．Ｔ．Ｂａｋｅｒ社（米国ニュージャージー州フィリップスバーグ））に移すことによって、チューブから残留試料を有効にすすいだ。試料を周囲温度で３０分間予備分解させてから、マイクロ波容器アセンブリを密閉し、ＭＡＲＳＸｐｒｅｓｓ（ＣＥＭ社（米国ノースカロライナ州マシューズ））装置中で１５分間１８０℃に昇温し、３０分間保持した。容器を室温に冷却してから、除圧及び内部標準として１％ＨＦ中に１００ｐｐｍ Ｎｂを２ｍＬ含む予め秤量した５０ｍＬ遠心チューブに移した。試料を１８ＭΩ脱イオン水を用いて２０ｍＬの総体積とし、マイクロ波容器を最低３回すすぎ、秤量した。 A representative section of tissue weighing approximately 500 mg was collected for microwave digestion and subsequent ICP-OES analysis. Samples were quantitatively transferred from a VWR® metal-free sterilized polypropylene 50 mL centrifuge tube to a pre-washed 100 mL CEM Corp XP-1500Plus ™ TFM ™ fluoropolymer microwave container liner. Sequential addition of solvent, vortexing and 2 mL 18 MΩ deionized water (DIW; Millipore (Bedford, MA)), 500 μL HF (46.0-51.0%) + 1 mL HNO 3 (70%) Ultrex® ) II ultra high purity reagent grade and 2 mL H 2 O 2 (30-32%) “Baker Analyzed” ® A. C. S. Residual samples were effectively rinsed from the tubes by transfer to reagent grade (JT Baker, Philipsburg, NJ, USA). The sample was pre-degraded at ambient temperature for 30 minutes before the microwave vessel assembly was sealed and heated to 180 ° C. for 15 minutes in a MARSXpress (CEM (Matthews, NC)) apparatus and held for 30 minutes. The container was cooled to room temperature and then transferred to a pre-weighed 50 mL centrifuge tube containing 2 mL of 100 ppm Nb in 1% HF as an internal standard. The sample was brought to a total volume of 20 mL using 18 MΩ deionized water and the microwave container was rinsed at least three times and weighed.
分析は表１に概説する機器条件下で実施し、２点バックグラウンド補正及び３０秒のソース平衡遅延を用いて１ピーク当たり３点のスペクトル条件で３回繰り返して収集した。５％ＨＮＯ3＋２％ＨＦ（Ａｌｆａ Ａｅｓａｒ社（米国マサチューセッツ州ワードヒル））ストック中Ｓｐｅｃｐｕｒｅ（登録商標）１００００μｇ／ｍＬ ＴａＣｌ5からの０．２〜１００ｐｐｍの０．５％ＨＦ中のマトリックス適合標準を較正として使用し、ストック１０ｍｇ／Ｌ（米国ニュージャージー州メアチェン）からの１ｐｐｍ ＳＰＥＸ ＣｅｒｔｉＰｒｅｐ（登録商標）Ｍｕｌｔｉ−ｅｌｅｍｅｎｔ Ｓｏｌｕｔｉｏｎ４を品質管理に使用した。５％ＨＮＯ3＋０．５％ＨＦのＩＣＰ−ＯＥＳリンス液を、各分析の間に４５秒間２．０ｍＬ／分の流速で流した。 The analysis was performed under the instrument conditions outlined in Table 1 and was collected in triplicate with 3 point spectral conditions per peak using 2 point background correction and 30 second source equilibration delay. Calibrate matrix fit standards in 0.2-100 ppm 0.5% HF from Specpure® 10000 μg / mL TaCl 5 in 5% HNO 3 + 2% HF (Alfa Aesar, Inc., Ward Hill, Mass.) Stock 1 ppm SPEX CertiPrep® Multi-element Solution 4 from the stock 10 mg / L (Merchen, NJ, USA) was used for quality control. 5% HNO 3 + 0.5% HF ICP-OES rinse was run at a flow rate of 2.0 mL / min for 45 seconds between each analysis.
２−ジエチルホスファトエチルシラン−ＴａＯとしても知られているＰＨＳ−Ｔａ2Ｏ5は、理想構造１５を有するナノ粒子を含むナノ粒子組成物であり、学術論文Ｉｎｖｅｓｔｉｇａｔｉｖｅ Ｒａｄｉｏｌｏｇｙ 第４７巻、第１０号、１〜１０頁、２０１２（その開示内容は援用によって本明細書の内容の一部をなす。）に記載されているように調製した。 PHS-Ta 2 O 5 , also known as 2-diethylphosphatoethylsilane-TaO, is a nanoparticle composition comprising nanoparticles having an ideal structure 15 and is a scientific paper Investigative Radiology Vol. 47, No. 10. 1-10, 2012 (the disclosure of which is incorporated herein by reference).
以上の実施例は、本発明の特徴の幾つかを例証するための例示にすぎない。添付の特許請求の範囲は考えられる限り広い範囲で本発明を特許請求するものであり、本明細書に記載した実施例は多種多様な実施形態から選択された実施形態を例示している。したがって、添付の特許請求の範囲は本発明の特徴を例示するために用いた実施例の選択によって限定されるべきでない。特許請求の範囲で用いる「含む」という用語は、論理的には、例えば特に限定されないが「から実質的になる」及び「からなる」のような様々な定義の異なる語句も包含して意味する。必要に応じて範囲を記載したが、これらの範囲は部分範囲を包含する。これらの範囲内での変動は当業者には自明であろうし、また未だ公表されていなくてもこれらの変動は可能であれば添付の特許請求の範囲に包含されると解すべきである。また、科学及び技術の進歩によって、言語の不正確さのために現在では想定されていない均等物及び代替物が可能になることも予想されるが、これらの変形例も可能であれば添付の特許請求の範囲に包含されると解すべきである。 The above examples are merely illustrative to illustrate some of the features of the present invention. The following claims are intended to claim the invention to the fullest extent possible, and the examples set forth herein illustrate embodiments selected from a wide variety of embodiments. Accordingly, the scope of the appended claims should not be limited by the choice of examples used to illustrate features of the present invention. As used in the claims, the term “comprising” means logically, including, but not limited to, different terms with various definitions such as “consisting essentially of” and “consisting of” . Ranges have been described where appropriate, but these ranges include subranges. Variations within these ranges will be apparent to those skilled in the art, and it should be understood that these variations are included in the appended claims if possible, even if not yet published. Scientific and technological advances are also expected to allow equivalents and alternatives not currently envisaged due to language inaccuracies. It should be understood that it is encompassed by the claims.
Claims (23)
The trialkoxysilane of claim 1, wherein each R 1 is methyl, each R 3 is hydrogen, and R 4 is 2-methyl-2-butyl.
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| JP6765098B2 (en) * | 2016-07-14 | 2020-10-07 | 国立研究開発法人産業技術総合研究所 | Magnetic nanoparticles immobilized imidazolium hydrogen carbonate |
| US20190001001A1 (en) * | 2017-07-03 | 2019-01-03 | General Electric Company | Drug design for application-dependent payload, controlled pharmacokinetic distribution, and renal clearance |
| CN111690006B (en) * | 2020-06-22 | 2023-07-14 | 宁波大学 | Imidazolyl-based ionic liquid material, preparation method thereof and application of imidazolyl-based ionic liquid material in phosphorylated peptide enrichment |
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